In:
Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 7, No. 2_Supplement ( 2019-02-01), p. A002-A002
Abstract:
Background: NY-ESO-1c259 is an affinity optimized TCR recognizing an NY-ESO-1-derived peptide complexed with HLA-A*02 (SPEAR T-cells). NY-ESO-1c259TCR therapy induced responses in ~50% of patients whose tumors express high level NY-ESO-1 (NCT01343043). Here we report on preclinical studies of TCR activity and results from a cohort of patients whose tumors express low NY-ESO-1 levels. Methods: T-cell response against tumor-derived cell lines with differential NY-ESO-1 expression levels was assessed by ELISA. Patients had selected HLA subtypes (HLA-A*02:01, 02:05, 02:06) and advanced NY-ESO-1+ SS. In this cohort, tumors express NY-ESO-1 at ≥ 1+ in & gt; 1% but & lt; 2+ or 3+ in ≥ 50% cells by immunohistochemistry (IHC). Following apheresis, T-cells are isolated, activated, transduced to express NY-ESO-1c259T and expanded. Lymphodepletion is with fludarabine 30 mg/m2/d × 4d and cyclophosphamide 1800 mg/m2/d × 2d. Target dose is 1–6 × 10e9 transduced cells. Disease is assessed at weeks 4, 8 and 12 and then every 3 months until disease progression. Results: NY-ESO-1c259T-cells produce IFNγ responses across a spectrum of NY-ESO-1 expressing tumor cell lines. A threshold for activation was observed at ~1×10e4 mRNA copies/10e6 reference gene transcripts. The IHC clinical trial assay was tested in FFPE tumor-derived cell lines, and staining was observed in cell lines expressing & gt;1×10e4 mRNA copies/10e6 reference gene transcripts. Ten patients in this cohort have been treated (as of 23Nov17). One died due to disease progression 2 days post infusion. Four have had a partial response (ORR 40%), and median duration of response was 8.5 weeks (range, 8-13). Antigen expression level by IHC (% 1+, 2+, and/or 3+), best overall response (BOR) by RECIST v1.1, and transduced cell expansion (copies/microgram DNA) are listed below for the 9 evaluable patients: Pt 264, 30% 1+/2+, PR, 86320; Pt 313, 90% 1+, PR, 45430; Pt 325, 10% 2+, PR, 13365; Pt 331, 40% 1+, 10% 2+, 10% 3+, PR, 197546; Pt 324, 50% 1+, 10% 2+, SD, 133334; Pt 305, 5% 1+, 5% 2+, 5% 3+, SD, 74855; Pt 322, 50% 1+, 10% 2+, SD, 54569; Pt 323, 20% 1+, 10% 2+, SD, 50912; Pt 211, 10% 1+, 20% 2+, 20% 3+, PD, 22627. Conclusions: In vitro assays can assess mRNA levels and protein expression of target antigen required for T-cell activation and cytotoxicity, predicting expression levels required for anti-tumor activity in vivo. The patient data suggest that affinity optimized TCRs can be used to treat tumors with low target antigen expression. Citation Format: Dejka Araujo, Sandra D'Angelo, George Demetri, Mihaela Druta, John Glod, Warren Chow, William Tap, Joana Senra, Rachel Abbott, Erin Van Winkle, Karen Chagin, Miguel Maroto, Elliot Norry, Malini Iyengar, Trupti Trivedi, Andrew Gerry, Rafael Amado, Crystal Mackall. Autologous Tcells transduced with the affinity enhanced NY-ESO-1c259TCR in patients with synovial sarcoma expressing low levels of the NY-ESO-1 antigen [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A002.
Type of Medium:
Online Resource
ISSN:
2326-6066
,
2326-6074
DOI:
10.1158/2326-6074.CRICIMTEATIAACR18-A002
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2019
detail.hit.zdb_id:
2732517-9
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